Chronic allopurinol administration ameliorates maladaptive alterations in Ca2+ cycling proteins and beta-adrenergic hyporesponsiveness in heart failure.

Xanthine oxidase (XO) activity contributes to both abnormal excitation-contraction (EC) coupling and cardiac remodeling in heart failure (HF). beta-Adrenergic hyporesponsiveness and abnormalities in Ca(2+) cycling proteins are mechanistically linked features of the HF phenotype. Accordingly, we hypothesized that XO influences beta-adrenergic responsiveness and expression of genes whose products participate in deranged EC coupling. We measured inotropic (dP/dt(max)), lusitropic (tau), and vascular (elastance; E(a)) responses to beta-adrenergic (beta-AR) stimulation with dobutamine in conscious dogs administered allopurinol (100 mg po daily) or placebo during a 4-wk induction of pacing HF. With HF induction, the decreases in both baseline and dobutamine-stimulated inotropic responses were offset by allopurinol. Additionally, allopurinol converted a vasoconstrictor effect to dobutamine to a vasodilator response and enhanced both lusitropic and preload reducing effects. To assess molecular correlates for this phenotype, we measured myocardial sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA), phospholamban (PLB), phosphorylated PLB (P-PLB), and Na(+)/Ca(2+) transporter (NCX) gene expression and protein. Although SERCA mRNA and protein concentrations did not change with HF, both PLB and NCX were upregulated (P < 0.05). Additionally, P-PLB and protein kinase A activity were greatly reduced. Allopurinol ameliorated all of these molecular alterations and preserved the PLB-to-SERCA ratio. Preventing maladaptive alterations of Ca(2+) cycling proteins represents a novel mechanism for XO inhibition-mediated preservation of cardiac function in HF, raising the possibility that anti-oxidant therapies for HF may ameliorate transcriptional changes associated with adverse cardiac remodeling and beta-adrenergic hyporesponsiveness.

A 32-year experience with surgical repair of sinus of valsalva aneurysms.

INTRODUCTION: Sinus of Valsalva (SoV) aneurysms are rare (0.15% to 1.5% CPB cases) and five times more frequent in Asians. Usually congenital, SoV aneurysms arise from the right or noncoronary sinus, are associated with other cardiac defects, and are repaired primarily or with a patch. Acquired SoV aneuryms develop secondary to infection or trauma. Here, we describe our 32-year experience with SoV aneurysm repair in a Western population. METHODS: A retrospective review identified 22 patients who underwent SoV aneurysm repair between 1971 and 2003. Data is presented as mean +/- standard error (median). RESULTS: Dyspnea was the most common presenting symptom. Nineteen of 22 patients were ruptured at the time of operation; three were found incidentally. Fifteen patients had associated cardiac defects including ventricular septal defect (VSD) (6), aortic insufficiency (6), and coarctation (3). One patient, repaired primarily, required reoperation for recurrence. All other patients underwent patch repair. The operative survival was 95% (21/22). There were five known late deaths at 6.6 +/- 2.3 (5.7) years post-repair. Five and ten year survival rates were 84.9 +/- 11% and 59.4 +/- 17%, respectively. CONCLUSION: Observed differences in the sinus of origin, age at presentation, associated cardiac malformations, and mortality in our Western series versus previous Asian cohort studies likely reflect a racial disparity and higher prevalence of acquired versus congenital SoV aneurysms. We recommend a thorough search for a VSD in all cases and use of patch repair, regardless of size, to reduce risk of recurrence.